In this study, we demonstrated that the patients with sarcopenia were significantly associated with poor OS and PFS compared to those without sarcopenia in BTC with distant metastasis at diagnosis. Furthermore, the patients with high NLR indicating inflammatory status play a significant role in OS and PFS. Based on these two results, we stratified the patients into 3 groups and there was a significant difference in OS and PFS between these groups. The patients with sarcopenia accompanied the inflammation showed inferior OS and PFS.
1. The sarcopenia affecting the prognosis
There is increasing evidence that the loss of muscle may affect the prognosis of cancer [5, 6]. As patients with malignancy are tended to be vulnerable to degenerative conditions, the decreased muscle mass and dysfunction are easily observed. Especially in malignancy progressed to unresectable or metastatic stage, the sarcopenia tend to occur often [29]. The relevance between sarcopenia and poor prognosis was shown in breast cancer [6], lung cancer [4], esophageal cancer [30], hepatocellular cancer [31], and colon cancer [32].
There is one article represented the relevance of sarcopenia and prognosis of patients with BTC. Yoon et al used two ways to evaluate the
25 sarcopenia status of patients; skeletal muscle attenuation and index. The author suggested that patients showing low skeletal muscle attenuation were associated with negative influence on survival those who underwent resection for BTC [33].
In our study, the sarcopenia alone did not worsen the PFS and OS in multivariate analysis. However, the patients with sarcopenia were significantly associated with poor prognosis in univariate analysis. Concordant with our data, in Yoon et al which analyzed about the significance of sarcopenia on BTC, low skeletal muscle index did not decreased the survival in multivariate survival [33]. It could be explained as the BTC is more affected by tumor specific factors rather than patient related factor such as sarcopenia.
There are controversial about the cut off values of sarcopenia to determine as there are several factors to consider such as the age, sex of patients, ethinicity, what level to be measured and which part of anatomy to be used. We adopted the cut off value of JSH guidelines which representing the Asian patients with liver disease [25]. As the amount of muscle waste is different depending on disease and ethinicity, further study would be helpful to clarify the cut off value of sarcopenia in metastatic biliary tract cancer.
2. The systemic inflammation affecting the prognosis
The systemic inflammation is a crucial parameter predicting cancer outcome in multiple cancers. Many inflammatory markers, such as CRP, NLR and PLR have been analyzed to find out the association between poor prognosis and various cancers [34-36].
Due to inflammatory response, the cytokines such as phosphatidylinositol 3-kinase, metalloproteinase-9 are recruited along the cancer, promote the proliferation of cancer cells and inhibit apoptosis of cancer cells [37]. Also, the cytokines promote the angiogenesis and tumor migration [38]. Based on these phenomena, the inflammation plays a key role in cancer progression. The high NLR associated with poor prognosis and poor response to treatment has been demonstrated in various cancer including melanoma [39], colorectal cancer [40, 41], intrahepatic cholangiocarcinoma [42], prostate cancer [43] and pancreatic cancer [44].
26 In biliary tract cancer, the NLR cut off value 3 is frequently used to evaluate the inflammatory status. Several studies compared the NLR>3 and NLR≤3 of OS in BTC. In these studies, the patients with NLR>3 showed poor OS compared to patients with NLR≤3 (Median OS; 21.6 months vs. 12.0 months, p=0.01). The patients with advanced stage were more predictive to NLR status than surgical group [26, 27]. In our study, the OS was significantly different depending NLR status.
3. The sarcopenia accompanied with systemic inflammation affecting the prognosis
Notably, patients with inflammation accompanied sarcopenia were associated with poor prognosis. These patients showed poor OS rates and also more disease progression than those without. The more studies demonstrating the relations between systemic inflammation and waste of muscle mass are systemic inflammation and sarcopenia are worsening each other.
The patients with sarcopenia in this study demonstrated high rate of inflammation such as CRP and NLR, and this reflects that sarcopenia are markers showing the increased activity of aggressive tumor [47]. The same result was demonstrated in head and neck cancer. Cho et al. represented that sarcopenia accompanied systemic inflammation was significantly associated with poor OS and PFS. Also, the patients with sarcopenia showed more frequent treatment interruption. Due to muscle wasting, the patients are hard to endure the treatment well [19].
In our study, the sarcopenia accompanied with systemic inflammation showed inferior OS and PFS. The poor treatment outcome could be explained because these patients may not tolerate well to treatment. For this reason, the sarcopenia did not lower the OS and PFS among the patients who received GP chemotherapy which is the 1st line chemotherapy. The patients who could tolerate the chemotherapy well received GP chemotherapy and among these patients, the sarcopenia did not significantly lower OS and PFS.
27 4. The SATI and VATI influence on prognosis
The other factors describing the adipose tissue composition of patients such as VATI and SATI were not associated with long-term survival in our study.
However, there are some reports demonstrating the high visceral fat is associated with poor survival in cancer patients [48]. The reason for opposite results could be explained that there are significantly less obese patients in Asia compared to patients in western. In other studies, patients showing overweight or obese status are over half of overall patients [49, 50]. In contrary, there are only 26.1% of patients representing overweight in our cohort. As the patients with high VATI was not sufficient, the VATI could not adversely affect the prognosis of cancer patients especially for Asian.
5. Limitation
There are some limitations in this study. First, the result should be interpreted with cautions due to its retrospective study nature. For example, we concluded that there is a relation between the sarcopenia, systemic inflammation and the survival. However, the causal relationship was not identified in this study. We could not demonstrate the cause and consequences of this phenomenon. Secondary, only the Korean patients were included in this study. The skeletal muscle mass are various depending on the disease, status of patients and ethnicity of patients. For this reason, the diverse cut-off values for sarcopenia are used. In this study, we adopted the sarcopenia definition created by the Japan Society of Hepatology (JSH). Yet, the optimal cut off value of sarcopenia for Korean cancer patients is rare. To evaluate the sarcopenia status for Korean population especially with malignancy, the further studies are necessary for new criteria of sarcopenia. Despite these limitation, this is the first study demonstrated the poor prognosis of sarcopenia accompanied systemic inflammation in metastatic BTC.